Commonly-used psychoactive prescription drugs such as opioids, antidepressants, benzodiazepines, and muscle relaxants are associated with unintentional traumatic injury?a major cause of morbidity, disability, and death. Given the increasing use of psychoactive prescription drugs, upsurge in persons with multiple chronic conditions, growth of polypharmacy, and aging of the US population, drug interactions are a major contributor to psychoactive drug-induced unintentional traumatic injury. Drug interactions cause significant preventable patient harm and represent a serious public health problem, especially in older adults, since age and polypharmacy are major risk factors. Known drug interactions are responsible for 13% of evident adverse drug events (ADEs) and 5% of hospital admissions in older adults, and >25% of community-residing elders will, in their lifetime, experience a clinically-significant ADE due to an interaction. Further, the risk of drug interactions is not limited to older adults, as one in four Americans has multiple chronic conditions, which drive polypharmacy. Therefore, the clinical and public health burden of drug interactions will continue to grow if not curtailed. This project's broad objective is to produce clinically-actionable and biologically-relevant knowledge about which medications interact with psychoactive prescription drugs to increase the risk of unintentional traumatic injury, as well as elucidate dose-response effects, duration-response effects, and subgroups most susceptible to the interactions. We will achieve this objective by: i) conducting high-throughput automated screening of longitudinal healthcare data to identify potential drug-drug and drug-drug-drug interactions involving opioids, antidepressants, benzodiazepines, and muscle relaxants that increase the risk of unintentional traumatic injury; ii) convene a multidisciplinary Expert Panel to review screening results, prioritize signals for further investigation, and set a priori hypotheses buttressed by putative mechanisms; and iii) conduct a series of rigorous pharmacoepidemiologic studies to inform causal inferences and thereby generate clinically-actionable evidence on drug interactions to prevent instances of unintentional traumatic injury.